Compositions and methods for treating purpura

ABSTRACT

Embodiments of the present invention are directed to compositions and methods for the treatment of purpura. Preferred compositions comprise an α adrenergic receptor agonist selected from selective α 1  adrenergic receptor agonist, selective α 2  adrenergic receptor agonist, non-selective α 1 /α 2  adrenergic receptor agonist, agents with α 2  adrenergic receptor agonist activity and combinations thereof, in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of hemorrhagic (purpuric) lesions in the skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/988,564 filed on Nov. 16, 2007, which is herein incorporated byreference in its entirety.

GOVERNMENT INTERESTS

Not applicable

PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable

BACKGROUND

1. Field of Invention

Not Applicable

2. Description of Related Art

Not Applicable

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present invention are directed to the use of an αadrenergic agonist for the treatment of vascular extravasation into theskin and particularly for the sequelae manifesting as cutaneouspetechiae, purpura or ecchymoses. The α adrenergic agonist may beselected from a selective α₁ adrenergic receptor agonist, selective α₂adrenergic receptor agonist, non-selective α₁/α₂ adrenergic receptoragonist, agents with α₂ adrenergic receptor agonist activity andcombinations thereof. The α adrenergic agonist may be administered to apatient in need thereof in a composition comprising a therapeuticallyeffective amount of the α adrenergic agonist, such as a composition fortopical administration.

Further embodiments of the present invention are directed to thetreatment of purpura in a subject comprising administering atherapeutically effective amount of an α adrenergic agonist to saidsubject, wherein the purpura is treated. In certain embodiments, the αadrenergic agonist may be selected from a selective α₁ adrenergicreceptor agonist, selective α₂ adrenergic receptor agonist,non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, the α adrenergic agonist may be administered to apatient in need thereof in a composition comprising a therapeuticallyeffective amount of the α adrenergic agonist. In certain embodiments,the composition may be suitable for topical administration or localadministration.

Further embodiments of the present invention are directed to theinhibition of purpura in a subject undergoing a surgical procedurecomprising administering a therapeutically effective amount of an αadrenergic agonist to said subject prior to, during or following thesurgical procedure, wherein the extent or amount of purpura generatedfollowing the surgical procedure is inhibited or decreased. In certainembodiments, the α adrenergic agonist may be selected from a selectiveα₁ adrenergic receptor agonist, selective α₂ adrenergic receptoragonist, non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, the α adrenergic agonist may be administered to apatient in a composition comprising a therapeutically effective amountof the α adrenergic agonist. In certain embodiments, the composition maybe suitable for topical administration or local administration.

DESCRIPTION OF DRAWINGS

Not Applicable

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers. Compoundsdescribed herein may contain an asymmetric center and may thus exist asenantiomers. Where the compounds according to the invention possess twoor more asymmetric centers, they may additionally exist asdiastereomers. The present invention includes all such possiblestereoisomers as substantially pure resolved enantiomers, racemicmixtures thereof, as well as mixtures of diastereomers. The formulas areshown without a definitive stereochemistry at certain positions. Thepresent invention includes all stereoisomers of such formulas andpharmaceutically acceptable salts thereof. Diastereoisomeric pairs ofenantiomers may be separated by, for example, fractional crystallizationfrom a suitable solvent, and the pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid or base as a resolvingagent or on a chiral HPLC column. Further, any enantiomer ordiastereomer of a compound of the general formula may be obtained bystereospecific synthesis using optically pure starting materials orreagents of known configuration.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “cell” is a reference to one or more cells and equivalents thereofknown to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient whereby the therapeutic positivelyimpacts the tissue to which it is targeted. Thus, as used herein, theterm “administering”, when used in conjunction with an α₁ or α₂adrenergic receptor agonist or composition thereof, can include, but isnot limited to, providing an α₁ or α₂ adrenergic receptor agonist orcomposition thereof into or onto the target tissue; or providing an α₁or α₂ adrenergic receptor agonist or composition thereof systemically toa patient by, e.g., intravenous injection whereby the therapeuticreaches the target tissue. Administering an α₁ or α₂ adrenergic receptoragonist or composition thereof may be accomplished by localadministration, such as injection directly into or around the site ofpurpura, topical administration, or by either method in combination withother known techniques

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics and/or the physicalattributes of the tissue to which it is being provided, applied oradministered. The change in form may be demonstrated by any of thefollowing alone or in combination: enhanced appearance of the skin;decrease in vascular extravasation into the skin; decrease in cutaneouspetechiae, purpura or ecchymoses; decrease in pigmentation; andhastening the resolution of the purpuric/hemorrhagic skin lesions.

The term “inhibiting” includes the administration of a compound of thepresent invention to prevent the onset of the symptoms, alleviating thesymptoms, or eliminating the disease, condition or disorder.

The term “patient” and “subject” are interchangeable and may be taken tomean any living organism which may be treated with compounds of thepresent invention. As such, the terms may include, but are not limitedto, any animal, mammal, primate or human, and preferably human.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

“Pharmaceutically acceptable salt” is meant to indicate those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.(1977) J. Pharm. Sciences, Vol 6. 1-19, describes pharmaceuticallyacceptable salts in detail.

For the purposes of this invention, a “salt” as used herein is any acidaddition salt, preferably a pharmaceutically acceptable acid additionsalt, including but not limited to, halogenic acid salts such as, forexample, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acidsalt; an inorganic acid salt such as, for example, nitric, perchloric,sulfuric and phosphoric acid salt; an organic acid salt such as, forexample, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic,ethanesulfonic, benzenesulfonic or p-toluenesulfonic), acetic, malic,fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic,pamoic, pantothenic, oxalic and maleic acid salts; and an amino acidsalt such as aspartic or glutamic acid salt. The acid addition salt maybe a mono- or di-acid addition salt, such as a di-hydrohalogenic,di-sulfuric, di-phosphoric or di-organic acid salt.

Unless otherwise indicated, the term “skin” means that outer integumentor covering of the body, consisting of the dermis and the epidermis andresting upon subcutaneous tissue.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of purpura or the decrease in vascular extravasation.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect, i.e., to decrease, block, or reverse purpura. The activitycontemplated by the present methods includes both medical therapeuticand/or prophylactic treatment, as appropriate. As used herein,“therapeutically effective amount” refers to the amount of activecompound or pharmaceutical agent that elicits a biological or medicinalresponse in a tissue, system, animal, individual or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes one or more of the following as specified in theparticular methodology: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reducing the severity of the pathology and/orsymptomatology). The specific dose of a compound administered accordingto this invention to obtain therapeutic and/or prophylactic effectswill, of course, be determined by the particular circumstancessurrounding the case, including, for example, the compound administered,the route of administration, and the condition being treated. Thecompounds are effective over a wide dosage range and, for example,dosages will normally fall within the range of from about 0.0025% toabout 5%, more usually in the range of from about 0.005% to about 2%,more usually in the range of from about 0.05% to about 1%, and moreusually in the range of form about 0.1% to about 0.5% by weight.However, it will be understood that the effective amount administeredwill be determined by the physician in the light of the relevantcircumstances including the condition to be treated, the choice ofcompound to be administered, and the chosen route of administration, andtherefore the above dosage ranges are not intended to limit the scope ofthe invention in any way. A therapeutically effective amount of compoundof this invention is typically an amount such that when it isadministered in a physiologically tolerable excipient composition, it issufficient to achieve an effective systemic concentration or localconcentration in the tissue.

The terms “treat,” “treated,” or “treating” as used herein refers toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects.

Generally speaking, the term “tissue” refers to any aggregation ofsimilarly specialized cells which are united in the performance of aparticular function.

As used herein, “α adrenergic agonist” refers to an α adrenergicagonist, a prodrug, congener or pharmaceutically acceptable salt thereofand may be selected from a selective α₁ adrenergic receptor agonist,selective α₂ adrenergic receptor agonist, non-selective α₁/α₂ adrenergicreceptor agonist, agents with α₂ adrenergic receptor agonist activityand combinations thereof. An α adrenergic agonist may be selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.Selective α₁ adrenergic receptor agonist may be selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, and amidephrine. Selective α₂ adrenergic receptor agonistmay be selected from brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, andα-methyldopa. Non-selective α₁/α₂ adrenergic receptor agonist may beselected from epinephrine, norepinephrine, isoproterenol, dipivefrin,pseudoephedrine, and mephentermine. Agents with α₂ adrenergic receptoragonist activity may be selected from phenylpropanolamine,propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine(deoxyepinephrine), ethylnorepinephrine, levarterenol(L-Norepinephrine), lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, and tizanidine.

Embodiments of the present invention are directed to the use of an αadrenergic agonist, or pharmaceutically acceptable salt thereof, for thetreatment of vascular extravasation into the skin and particularly forthe sequelae manifesting as cutaneous petechiae, purpura or ecchymoses.In certain embodiments, the α adrenergic agonist may be selected from aselective α₁ adrenergic receptor agonist, selective α₂ adrenergicreceptor agonist, non-selective α₁/α₂ adrenergic receptor agonist,agents with α₂ adrenergic receptor agonist activity and a combinationthereof. Preferably, the α adrenergic agonist is administered to apatient in a composition, preferably for topical or local administrationto a patient in need thereof. In embodiments of the present invention,the α adrenergic agonist may be selected from oxymetazoline,naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Embodiments of the present invention are directed toward the use ofcomposition comprised of an α adrenergic agonist, which may be selectedfrom a selective α₁ adrenergic receptor agonist, selective α₂ adrenergicreceptor agonist, non-selective α₁/α₂ adrenergic receptor agonist,agents with α₂ adrenergic receptor agonist activity and a combinationthereof in a pharmaceutically acceptable carrier in order to treat andimprove the cosmetic appearance of these hemorrhagic lesions. Inembodiments of the present invention, the α adrenergic agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, α-methyldopa, epinephrine, norepinephrine,isoproterenol, dipivefrin, pseudoephedrine, mephentermine,phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine,ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol(L-Norepinephrine), lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.Selective α₁ adrenergic receptor agonist may be selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, and amidephrine. In further embodiments, α₁-adrenergicreceptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

As used herein, the term “purpura” refers to any accumulation of bloodin the skin due to vascular extravasation, irrespective of size orcause. As used herein, “purpura” refers to medical conditions commonlyreferred to as “petechiae” (pinpoint spots), “ecchymoses” (largermacular (flat) patches) and “purpura” (larger spots).

Purpura, in general, is hemorrhage of blood out of the vascular spacesand into the surrounding tissues of the skin or mucous membranes. Thishemorrhage results in a collection of blood in the dermis of the skinthat is visible initially as a dark purple/red discoloration thatchanges color as it breaks down and is resorbed.

In particular, purpura can be characterized as flat (macular ornon-palpable) or raised (palpable or papular). The definition of macularpurpuric subtypes include: Petechiae-defined as small purpura (less than4 millimeters (mm) in diameter, purpura-defined as greater than 4 mm andless than 1 cm (centimeter) in diameter, and ecchymoses-defined asgreater than 1 cm in diameter. The size divisions are not absolute butare useful rules of thumb and there is often a range in size of clinicalpurpuras in any one specific condition.

A bruise, also called a contusion or ecchymosis, is an injury tobiological tissue in which the capillaries are damaged, allowing bloodto seep into the surrounding tissue. Bruising is usually caused by ablunt impact and its likelihood and its severity increases as one agesdue to thinning and loss of elasticity of the skin.

While not wishing to be bound by theory, we believe that by virtue ofthe fact that these compounds cause local vasoconstriction and ashunting of the blood back to deeper vessels due to their activity atthe vascular α adrenergic receptors, their use may decrease theaccumulation of blood (and hemosiderin, which is responsible for along-lasting deep brown color) in the skin, resulting in a cosmeticimprovement in these conditions.

Initially classified as either α or β subtype receptors based onanatomical location and functional considerations, in recent years, andwith newer molecular genetic techniques, the simple model of twoadrenergic receptors (adrenergic receptors) that mediate the vascularresponse to catecholamines has been replaced. The concept of “generic” αreceptors, responsible mostly for “excitatory” functions such asvasoconstriction, uterine and urethral contraction and “generic” βreceptors, responsible mostly for “inhibitory” functions such asvasodilatation, bronchodilation, uterine and urethral relaxation (thoughnotably inotropic for the heart) has been further refined and specificreceptor subtypes, localizations and functions have been elucidated. Thecurrent model is that of a complex family of structurally relatedreceptors consisting of at least six a receptor subtypes (α_(1A)(α_(1a/c)), α_(1B), α_(1D), α_(2A) (α_(2A/D)), α_(2B), α_(2C)) and atleast three β receptor subtypes (β₁, β₂, β₃), with additionalconformational variants such as α_(1L) and β₄ bringing the total numberof functional adrenergic receptor conformations to at least 11.

These adrenergic receptors are all members of the G-protein-coupledreceptor (GPCR) superfamily of proteins and modulate their effectsthrough a classic 7-transmembrane protein second-messenger system. Theirfinal local and systemic effects however are myriad, as noted above,including vasoactive properties ranging from vasoconstriction tovasodilatation and occur through a wide variety of intracellularmechanisms, that are governed by local receptor subtype concentration,relative receptor subtype distribution throughout the body, ligandbinding characteristics and other factors (e.g. local temperature,hypoxia). Elegant in vitro, in vivo and ex vivo studies in a variety ofvascular tissues and species reveal that the contraction of peripheralvascular smooth muscle is primarily mediated by α_(1A) and α_(1D)receptor subtypes, though does vary somewhat in different vascularregions. α₂ receptor studies suggest that α_(2A/D) and α_(2B) effectsare also of importance, particularly on the arterial side, and that theα_(2A/D) and α_(2C) effects are of importance on the venular side,though variations based on the experimental model employed are wellreported. The actual physiologic and clinical responses to stimulatingor inhibiting these receptors selectively is, however, difficult topredict.

Though initially felt to modulate their effects purely through theirvasoconstrictive properties, in recent years it has been demonstratedthat several of the α vasoconstrictors also exhibit significantanti-inflammatory properties. In upper respiratory tract infections,oxymetazoline and xylometazoline have been shown to inhibit neutrophilicphagocytosis and oxidative burst, resulting in a decrease in microbialkilling, decreased generation of pro-inflammatory cytokines, anddecreased inflammation. Oxymetazoline has also recently been shown tohave significant effects on the arachadonic acid cascade, stronglyinhibiting 5-lipoxygenase activity thus decreasing the synthesis of thehighly proinflammatory leukotriene B₄. A potential clinical role foroxymetazoline, or other agents of this class, as inhibitors ofinflammation and oxidative-stress dependent reactions in inflammatoryand/or infectious skin conditions is intriguing, but has yet to beinvestigated.

Further embodiments of the present invention provide methods andcompositions for treating purpura and other conditions of the skincharacterized by intradermal cutaneous hemorrhages (e.g., petechiae,purpura, ecchymoses) by administering an α adrenergic receptor agonistto a patient in need thereof. In certain embodiments, the α adrenergicagonist may be selected from a selective α₁ adrenergic receptor agonist,selective α₂ adrenergic receptor agonist, non-selective α₁/α₂ adrenergicreceptor agonist, agents with α₂ adrenergic receptor agonist activityand combinations thereof. In certain embodiments, a therapeuticallyeffective amount of selective α₁ adrenergic receptor agonist, selectiveα₂ adrenergic receptor agonist, non-selective α₁/α₂ adrenergic receptoragonist, agents with α₂ adrenergic receptor agonist activity andcombinations thereof is administered. In certain embodiments, the αadrenergic receptor agonist is administered topically or locally to thepatient. In embodiments of the present invention, the α adrenergicagonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Another embodiment of the present invention provides methods andcompositions for treating other conditions of the skin characterized byintradermal hemorrhage and skin discoloration due to the resorption ofthe intracutaneous blood accumulation comprising administering an αadrenergic receptor agonist to a patient in need thereof. In certainembodiments, the α adrenergic agonist may be selected from a selectiveα₁ adrenergic receptor agonist, selective α₂ adrenergic receptoragonist, non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, a therapeutically effective amount of the αadrenergic receptor agonist is administered. In certain embodiments, theα adrenergic receptor agonist is administered topically or locally tothe patient. In embodiments of the present invention, the α adrenergicagonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Another embodiment of the present invention provides methods andcompositions for improvement of bruising comprising administering an αadrenergic receptor agonist to a patient in need thereof. In certainembodiments, the α adrenergic agonist may be selected from a selectiveα₁ adrenergic receptor agonist, selective α₂ adrenergic receptoragonist, non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, a therapeutically effective amount of the αadrenergic receptor agonist is administered. In certain embodiments, theα adrenergic receptor agonist is administered topically or locally tothe patient. In embodiments of the present invention, the α adrenergicagonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Other embodiments of the present invention are methods and compositionsfor treating the cutaneous manifestations of intrinsic (chronological)and extrinsic (e.g. caused by sun exposure, smoking, etc) aging of theskin including, but not limited to, purpura (or “bruising”), skinwrinkling, sallow-yellow skin discoloration, dark circles under theeyes, bruising, bruising caused by laser administration, andhyperpigmentation comprising administering an α adrenergic receptoragonist to a patient in need thereof. In certain embodiments, the αadrenergic agonist may be selected from a selective α₁ adrenergicreceptor agonist, selective α₂ adrenergic receptor agonist,non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, a therapeutically effective amount of the αadrenergic receptor agonist is administered. In certain embodiments, theα adrenergic receptor agonist is administered topically or locally tothe patient. In embodiments of the present invention, the α adrenergicagonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Further embodiment of the present invention provides methods andcompositions for decreasing bruising caused by laser by administering anα adrenergic receptor agonist to a patient in need thereof prior to orsoon after laser treatment. In certain embodiments, the α adrenergicagonist may be selected from a selective α₁ adrenergic receptor agonist,selective α₂ adrenergic receptor agonist, non-selective α₁/α₂ adrenergicreceptor agonist, agents with α₂ adrenergic receptor agonist activityand combinations thereof. In certain embodiments, a therapeuticallyeffective amount of the α adrenergic receptor agonist is administered.In certain embodiments, the α adrenergic receptor agonist isadministered topically or locally to the patient. In embodiments of thepresent invention, the α adrenergic agonist may be selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Further embodiments of the present invention provide methods andcompositions for resolving purpura using such a laser or a non-laserlight source in combination with an α₁ adrenergic receptor agonist, anα₂ adrenergic receptor agonist or a combination thereof to a patient inneed thereof prior to, during or following the use of such a laser. Incertain embodiments, the α adrenergic agonist may be selected from aselective α₁ adrenergic receptor agonist, selective α₂ adrenergicreceptor agonist, non-selective α₁/α₂ adrenergic receptor agonist,agents with α₂ adrenergic receptor agonist activity and combinationsthereof. In certain embodiments, a therapeutically effective amount ofthe α adrenergic receptor agonist is administered. In certainembodiments, the α adrenergic receptor agonist is administered topicallyor locally to the patient. In embodiments of the present invention, theα adrenergic agonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Further embodiments of the present invention provide methods andcompositions for treatment of purpura conditions caused by a surgicalprocedure involving physical trauma to the skin and/or cutaneousvasculature. As used herein, the term surgical procedure refers to anyintervention that may result in an injury to biological tissue in whichthe skin, cutaneous and subcutaneous vascular and surrounding tissuesmight sustain injury that would allow blood to seep into the surroundingtissue. Such interventions include, but are not limited to needle-sticks(e.g. for phlebotomy or infusion), injection of therapeutic agents (e.g.vaccines or sclerotherapy, injection of neurotoxins or fillers forsoft-tissue augmentation, cold-steel surgery (e.g. “incisional” or“excisional” surgery), “minimally-invasive” procedures (e.g.laparoscopic, arthroscopic procedures, liposuction), laser, thermal,intense pulsed light (IPL), other electromagnetic radiation-basedprocedures, radiofrequency, chemical, electro-surgical and ultrasonicprocedures. In such embodiments, a therapeutically effective amount ofthe α adrenergic receptor agonist, is administered to a patient priorto, during and/or after said surgical procedure, such that the formationof purpura (extent, duration, amount, size) is inhibited or decreased.In certain embodiments, the α adrenergic agonist may be selected from aselective al adrenergic receptor agonist, selective α₂ adrenergicreceptor agonist, non-selective α₁/α₂ adrenergic receptor agonist,agents with α₂ adrenergic receptor agonist activity and combinationsthereof. In certain embodiments, a therapeutically effective amount ofthe α adrenergic receptor agonist is administered. In certainembodiments, the α adrenergic receptor agonist is administered topicallyor locally to the patient. In embodiments of the present invention, theα adrenergic agonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Further embodiments of the present invention provide methods andcompositions for preventing purpura caused by a surgical procedureinvolving physical trauma to the skin and/or cutaneous vasculature, suchas, for example, external blunt-force trauma, internal blunt-forcetrauma (e.g. liposuction trauma or surgical undermining trauma), “sharp”trauma (e.g. skin incision, skin puncture, needle stick), laceration,dermabrasion, chemical burn, thermal burn, and electrical burn. In suchembodiments, a therapeutically effective amount of the α adrenergicreceptor agonist, is administered to a patient prior to, during and/orafter said surgical procedure, such that the formation of purpura(extent, duration, amount, size) is prevented. In certain embodiments,the α adrenergic agonist may be selected from a selective α₁ adrenergicreceptor agonist, selective α₂ adrenergic receptor agonist,non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. Incertain embodiments, a therapeutically effective amount of the αadrenergic receptor agonist is administered. In certain embodiments, theα adrenergic receptor agonist is administered topically or locally tothe patient. In embodiments of the present invention, the α adrenergicagonist may be selected from oxymetazoline, naphazoline,tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, α-methyldopa, epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine andcombinations thereof. Selective α₁ adrenergic receptor agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, and amidephrine. In further embodiments,α₁-adrenergic receptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride. Selective α₂adrenergic receptor agonist may be selected from brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, and α-methyldopa. In further embodiments, α₂-adrenergicreceptor agonist is preferably brimonidine. Non-selective α₁/α₂adrenergic receptor agonist may be selected from epinephrine,norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, andmephentermine. Agents with α₂ adrenergic receptor agonist activity maybe selected from phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine (deoxyepinephrine),ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,methamphetamine, α-methylnorepinephrine, methylphenidate, mivazerol,moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.

Further embodiments of the present invention provide compositionscomprising at least one α₁ adrenergic receptor agonist and/or at leastone α₂ adrenergic receptor agonist, alone or in combination, into acosmetic, pharmaceutical or dermatological composition for decreasingand/or preventing purpura and other conditions of the skin characterizedby intradermal cutaneous hemorrhages and to administer said compositionsto a mammal, notably a human, in order to treat or prevent the diseasestates indicated above.

Further embodiments of the present invention provide compositionscomprising at an α adrenergic receptor agonist in a cosmetic,pharmaceutical or dermatological composition for decreasing and/orpreventing purpura and other conditions of the skin characterized byintradermal cutaneous hemorrhages. In certain embodiments, the αadrenergic receptor agonist may be selected from a selective α₁adrenergic receptor agonist, selective α₂ adrenergic receptor agonist,non-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof. In someembodiments, the composition may further comprise other agents known tobe effective in treating purpura.

Embodiments of the present invention are directed to methods fortreating purpura and other conditions of the skin characterized byintradermal cutaneous hemorrhages in a patient in need of suchtreatment, comprising the administration, preferably topical or local,of a therapeutically effective amount of a composition comprising anα-adrenergic receptor agonist. In certain embodiments, the α adrenergicagonist may be selected from a selective α₁ adrenergic receptor agonist,selective α₂ adrenergic receptor agonist, non-selective α₁/α₂ adrenergicreceptor agonist, agents with α₂ adrenergic receptor agonist activityand combinations thereof.

In embodiments of the present invention, the α adrenergic agonist may beselected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,dexmedetomidine, α-methyldopa, epinephrine, norepinephrine,isoproterenol, dipivefrin, pseudoephedrine, mephentermine,phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine,ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol(L-Norepinephrine), lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.

Selective α₁ adrenergic receptor agonist may be selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, and amidephrine. In further embodiments, α₁-adrenergicreceptor agonist is preferably oxymetazoline, naphazoline,tetrahydrozoline, and phenylephrine hydrochloride.

Selective α₂ adrenergic receptor agonist may be selected frombrimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine,medetomidine, dexmedetomidine, and α-methyldopa. In further embodiments,α₂-adrenergic receptor agonist is preferably brimonidine.

Non-selective α₁/α₂ adrenergic receptor agonist may be selected fromepinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,and mephentermine.

Agents with α₂ adrenergic receptor agonist activity may be selected fromphenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine,ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol(L-Norepinephrine), lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, and tizanidine.

Preferably, the composition comprises at least one selective α₁adrenergic receptor agonist, selective α₂ adrenergic receptor agonist,non-selective α₁/α₂ adrenergic receptor agonist, and agents with α₂adrenergic receptor agonist activity formulated in a pharmaceuticallyacceptable medium. For example, a gel, cream, lotion or solution whichmay be administered by spreading the gel, cream, lotion or solution ontoor surrounding the affected area.

Other embodiments may also include combinations of therapeuticallyeffective amounts of combinations of a selective α₁ adrenergic receptoragonist, a selective α₂ adrenergic receptor agonist, a non-selectiveα₁/α₂ adrenergic receptor agonist, and agents with α₂ adrenergicreceptor agonist activity. The therapeutically effective amount of eachagent may be significantly decreased when used in combination with otherα-adrenergic receptor agonist than when used as the sole active agent.

Preferred embodiments may also include enhancers of cutaneouspenetration or inhibitors or regulators of cutaneous penetration asrequired to increase therapeutic efficacy and/or decrease systemicabsorption and any potential undesirable systemic effects of the activeagent(s).

Further embodiments of the present invention provide methods of treatingsuch conditions by administering one or more α₁-adrenergic receptoragonists alone or in combination with one or more and α₂-adrenergicreceptor agonists (alone or in combination) with active agents forpreventing and/or treating other skin complaints, conditions andafflictions. Examples of these agents include: (i) antirosacea agentssuch as metronidazole, precipitated sulfur, sodium sulfacetamide, orazelaic acid; (ii) antibacterial agents (antibiotics) such asclindamycin phosphate, erythromycin, or antibiotics from thetetracycline family; (iii) antimycobacterial agents such as dapsone;(iv) antiacne agents such as retinoids, or benzoyl peroxide; (v)antiparasitic agents such as metronidazole, permethrin, crotamiton orpyrethroids; (vi) antifungal agents such as compounds of the imidazolefamily such as miconazole, clotrimazole, econazole, ketoconazole, orsalts thereof, polyene compounds such as amphotericin B, compound of theallylamine family such as terbinafine; (vii) steroidal anti-inflammatoryagents such as hydrocortisone triamcinolone, fluocinonide, betamethasonevalerate or clobetasol propionate, or non-steroidal anti-inflammatoryagents such as ibuprofen and salts thereof, naproxen and salts thereof,or acetaminophen; (viii) anesthetic agents such as lidocaine,prilocaine, tetracaine, hydrochloride and derivatives thereof; (ix)antipruriginous agents such as thenaldine, trimeprazine, or pramoxine;(x) antiviral agents such as acyclovir; (xi) keratolytic agents such asalpha- and beta-hydroxy acids such as glycolic acid or salicylic acid,or urea; (xii) anti-free radical agents (antioxidants) such as vitamin E(alpha tocopherol) and its derivatives, vitamin C (ascorbic acid),vitamin A (retinol) and its derivatives, vitamin K, superoxide dismutaseand derivatives of plants, particularly of the genus Arnica, such assesquiterpene lactones (xiii) antiseborrheic agents such as zincpyrithione and selenium sulfide; (xiv) antihistamines such ascyproheptadine or hydroxyzine; (xv) tricyclic antidepressants such asdoxepin hydrochloride and (xvi) combinations thereof.

For example, in some aspects, the invention is directed to apharmaceutical composition comprising a selective α₁ adrenergic receptoragonist, a selective α₂ adrenergic receptor agonist, a non-selectiveα₁/α₂ adrenergic receptor agonist, agents with α₂ adrenergic receptoragonist activity and combinations thereof and a pharmaceuticallyacceptable carrier or diluent, or an effective amount of apharmaceutical composition comprising a compound as defined above.

The compositions may be formulated to be administered orally,ophthalmically, intravenously, intramuscularly, intra-arterially,intramedularry, intrathecally, intraventricularly, transdermally,subcutaneously, intraperitoneally, intravesicularly, intranasally,eternally, topically, sublingually, or rectally, preferably topically orlocally.

Embodiments of the invention include compositions comprising an αadrenergic receptor agonist, preferably a selective α₁ adrenergicreceptor agonist, a selective α₂ adrenergic receptor agonist, anon-selective α₁/α₂ adrenergic receptor agonist, agents with α₂adrenergic receptor agonist activity and combinations thereof.Preferably the compositions may be administered topically or locally.The compounds of the present invention can be administered in theconventional manner by any route where they are active. Administrationcan be systemic, topical, or oral. For example, administration can be,but is not limited to, parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, oral, buccal, or ocularroutes, or intravaginally, intravesicularly, by inhalation, by depotinjections, or by implants. Thus, modes of administration for thecompounds of the present invention (either alone or in combination withother pharmaceuticals) can be, but are not limited to, sublingual,injectable (including short-acting, depot, implant and pellet formsinjected subcutaneously or intramuscularly), or by use of vaginalcreams, suppositories, pessaries, vaginal rings, rectal suppositories,intrauterine devices, and transdermal forms such as patches and creams.

One of ordinary skill in the art will understand and appreciate thedosages and timing of said dosages to be administered to a patient inneed thereof. The doses and duration of treatment may vary, and may bebased on assessment by one of ordinary skill in the art based onmonitoring and measuring improvements in skin tissues. This assessmentmay be made based on outward physical signs of improvement, such asdecreased redness, or other physiological signs or markers. The dosesmay also depend on the condition or disease being treated, the degree ofthe condition or disease being treated and further on the age and weightof the patient.

Specific modes of administration will depend on the indication. Theselection of the specific route of administration and the dose regimenmay be adjusted or titrated by the clinician according to methods knownto the clinician in order to obtain the optimal clinical response. Theamount of compound to be administered may be that amount which istherapeutically effective. The dosage to be administered may depend onthe characteristics of the subject being treated, e.g., the particularanimal or human subject treated, age, weight, health, types ofconcurrent treatment, if any, and frequency of treatments, and can beeasily determined by one of skill in the art (e.g., by the clinician).

A preferable route of administration of the compositions of the presentinvention may be topical or local.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or acetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Pharmaceutical formulations comprising the compounds of the presentinvention and a suitable carrier may also be any number of solid dosageforms which include, but are not limited to, tablets, capsules, cachets,pellets, pills, powders and granules; topical dosage forms whichinclude, but are not limited to, solutions, powders, fluid emulsions,fluid suspensions, semi-solids, ointments, pastes, creams, gels andjellies, and foams; and parenteral dosage forms which include, but arenot limited to, solutions, suspensions, emulsions, and dry powder;comprising an effective amount of a polymer or copolymer of the presentinvention. It is also known in the art that the active ingredients canbe contained in such formulations with pharmaceutically acceptablediluents, fillers, disintegrants, binders, lubricants, surfactants,hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,humectants, moisturizers, solubilizers, preservatives and the like. Themeans and methods for administration are known in the art and an artisancan refer to various pharmacologic references for guidance. For example,Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); andGoodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6thEdition, MacMillan Publishing Co., New York (1980) can be consulted.

The compounds of the present invention can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. The compounds can be administered by continuous infusion overa period of about 15 minutes to about 24 hours. Formulations forinjection can be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. The compositions cantake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and can contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

For oral administration, the compounds can be formulated readily bycombining these compounds with pharmaceutically acceptable carriers wellknown in the art. As used herein, the term “pharmaceutically acceptablecarrier” means a non-toxic, inert solid, semi-solid liquid filler,diluent, encapsulating material, formulation auxiliary of any type, orsimply a sterile aqueous medium, such as saline. Some examples of thematerials that can serve as pharmaceutically acceptable carriers aresugars, such as lactose, glucose and sucrose, starches such as cornstarch and potato starch, cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt, gelatin, talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such aspropylene glycol, polyols such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters such as ethyl oleate and ethyl laurate,agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer'ssolution; ethyl alcohol and phosphate buffer solutions, as well as othernon-toxic compatible substances used in pharmaceutical formulations.Such carriers enable the compounds of the invention to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a patient to be treated.Pharmaceutical preparations for oral use can be obtained by adding asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations such as, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with filler such as, e.g., lactose, binders such as, e.g.,starches, and/or lubricants such as, e.g., talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds canbe dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers can be added. All formulations for oral administrationshould be in dosages suitable for such administration.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

For buccal or sublingual administration, the compositions can take theform of tablets, flash melts or lozenges formulated in any conventionalmanner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds of the present invention can also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds ofthe present invention can also be formulated as a depot preparation.Such long acting formulations can be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection.

Depot injections can be administered at about 1 to about 6 months orlonger intervals. Thus, for example, the compounds can be formulatedwith suitable polymeric or hydrophobic materials (for example, as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, for example, as a sparingly soluble salt.

In transdermal administration, the compounds of the present invention,for example, can be applied to a plaster, or can be applied bytransdermal, therapeutic systems that are consequently supplied to theorganism.

Pharmaceutical and therapeutic compositions of the compounds also cancomprise suitable solid or gel phase carriers or excipients. Examples ofsuch carriers or excipients include, but are not limited to, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as, e.g., polyethylene glycols.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification.

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts whichcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not limit the scope of the invention.Various modifications and combinations of the illustrative embodiments,as well as other embodiments of the invention, will be apparent topersons skilled in the art upon reference to the description.

EXAMPLE 1

In order to evaluate the effect of topically applied α₁ and α₂adrenergic agonists on the resolution of purpura, purpuricmacules/patches were experimentally created on the trunk of a volunteer.Seven sites were marked, and utilizing a pulsed-dye laser (585 nm) andlaser light parameters known to be purpurogenic, purpuricmacules/patches were successfully induced at each site. Immediatelyafter the laser energy was delivered, the topical application ofcommercially available α₁ and/or α₂ adrenergic agonist preparations wasbegun. The preparations were applied to the skin and gently rubbed onthe skin over and immediately surrounding the laser treatment sitesevery 6-8 hours (3-4 times/day). The applied solution was allowed toair-dry without any dressing. The areas were followed clinically andphotographically. The evaluated compounds were:

Site 1: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazolinehydrochloride 0.05% (Afrin® Original 12 Hour Nasal Spray(Schering-Plough Healthcare Products) containing: oxymetazolinehydrochloride 0.05%, benzalkonium chloride solution, edetate disodium,polyethylene glycol, povidone, propylene glycol, purified water, sodiumphosphate dibasic, sodium phosphate monobasic.

Site 2: Naphazoline hydrochloride (0.03%): A solution of naphazolinehydrochloride 0.03% (Clear Eyes® Maximum Redness Relief (Prestige BrandsInc.) containing: naphazoline hydrochloride 0.03%, glycerin 0.5%,benzalkonium chloride, boric acid, edetate disodium, purified water,sodium borate).

Site 3: Tetrahydrozoline hydrochloride (0.05%): A solution oftetrahydrozoline hydrochloride 0.05% (Visine® Original (Pfizer ConsumerHealthcare) containing: tetrahydrozoline hydrochloride 0.05%,benzalkonium chloride, boric acid, edetate disodium, purified water,sodium borate, sodium chloride).

Site 4: Phenylephrine hydrochloride (1.0%): A solution of phenylephrinehydrochloride 1.0% (Neo-Synephrine® Extra Strength Spray (BayerHealthCare) containing: phenylephrine hydrochloride 1.0%, anhydrouscitric acid, benzalkonium chloride, sodium chloride, sodium citrate,water).

Site 5: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate0.2% (Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citricacid, polyvinyl alcohol, sodium chloride, sodium citrate, purifiedwater, benzalkonium chloride (0.005%).

Site 6: Oxymetazoline hydrochloride 0.05% and brimonidine tartrate 0.2%:The solution of oxymetazoline hydrochloride 0.05% (Afrin® (Original 12Hour Nasal Spray (Schering-Plough Healthcare Products) containing:oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,edetate disodium, polyethylene glycol, povidone, propylene glycol,purified water, sodium phosphate dibasic, sodium phosphate monobasic wasapplied first, then was followed by the application of the solution ofbrimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing: brimonidinetartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodiumcitrate, purified water, benzalkonium chloride (0.005%).

Site 7: No treatment after laser light delivered. (“Control”)

The sites were followed clinically and photographically 1, 3, 4, 6, 11and 13 days after the creation of the purpura. In each of the sitestreated with at least one of the α agonist preparations, the resolutionof the purpura was more rapid than in the non-treated control site. Thiseffect was most pronounced on site 2 (naphazoline 0.03%), site 4(phenylephrine 1.0%), site 1 (oxymetazoline 0.05%), and site 6(oxymetazoline hydrochloride 0.05%+brimonidine tartrate 0.2%). No localor systemic side effects were noted, and in particular, there was norebound erythema or edema noted.

These trials demonstrate that selective α₁ adrenergic receptor agonistsand selective α₂ adrenergic receptor agonists, used separately or incombination, when topically applied to and around a treatment site aftera procedure that can/will induce purpura, will reduce the size andappearance of the purpuric macules/patches and is an effective treatmentto hasten their resolution.

EXAMPLE 2

In order to evaluate the effect of topically applied α₁ and α₂adrenergic agonists on the prevention of laser-induced purpura on normalnon-actinically damaged skin, seven sites on the trunk of a volunteerwere marked and treated with the topical application of a commerciallyavailable α₁ and/or α₂ agonist preparation. Six (of the seven) markedsites were pretreated with the topical application of at least one ofthe testing preparations. The preparations were applied to the skin andgently rubbed on the skin over and immediately surrounding the lasertreatment sites 3 hours prior to and 1 hour prior to the delivery of thelaser energy. The applied solution was allowed to air-dry without anydressing. Utilizing a pulsed-dye laser (585 nm) and laser lightparameters known to be purpurogenic, purpuric macules/patches weresuccessfully induced at each site. After the delivery of the laserenergy, each spot received only topical petrolatum jelly 3-4 times/dayand no additional application of any testing compound. The sites werefollowed clinically and photographically 1, 3, 4, 6, 11 and 13 daysafter the creation of the purpura. The evaluated compounds were:

Site 8: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazolinehydrochloride 0.05% (Afrin® Original 12 Hour Nasal Spray(Schering-Plough Healthcare Products) containing: oxymetazolinehydrochloride 0.05%, benzalkonium chloride solution, edetate disodium,polyethylene glycol, povidone, propylene glycol, purified water, sodiumphosphate dibasic, sodium phosphate monobasic.

Site 9: Naphazoline hydrochloride (0.03%): A solution of naphazolinehydrochloride 0.03% (Clear Eyes® Maximum Redness Relief (Prestige BrandsInc.) containing: naphazoline hydrochloride 0.03%, glycerin 0.5%,benzalkonium chloride, boric acid, edetate disodium, purified water,sodium borate).

Site 10: Tetrahydrozoline hydrochloride (0.05%): A solution oftetrahydrozoline hydrochloride 0.05% (Visine® Original (Pfizer ConsumerHealthcare) containing: tetrahydrozoline hydrochloride 0.05%,benzalkonium chloride, boric acid, edetate disodium, purified water,sodium borate, sodium chloride).

Site 11: Phenylephrine hydrochloride (1.0%): A solution of phenylephrinehydrochloride 1.0% (Neo-Synephrine® Extra Strength Spray (BayerHealthCare) containing: phenylephrine hydrochloride 1.0%, anhydrouscitric acid, benzalkonium chloride, sodium chloride, sodium citrate,water).

Site 12: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate0.2% (Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citricacid, polyvinyl alcohol, sodium chloride, sodium citrate, purifiedwater, benzalkonium chloride (0.005%).

Site 13: oxymetazoline hydrochloride 0.05% and brimonidine tartrate0.2%: The solution of oxymetazoline hydrochloride 0.05% (Afrin® Original12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing:oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,edetate disodium, polyethylene glycol, povidone, propylene glycol,purified water, sodium phosphate dibasic, sodium phosphate monobasic wasapplied first, then was followed by the application of the solution ofbrimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing: brimonidinetartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodiumcitrate, purified water, benzalkonium chloride (0.005%).

Site 14: No treatment after laser light delivered. (“Control”)

In each of the sites treated with at least one of the α agonistpreparations prior to the delivery of the laser energy, the purpuricmacule/patch created was smaller than in the non pre-treated site. Thetime course of the resolution of the purpura was shortened as well. Thiseffect was more pronounced on the sites pretreated with oxymetazolinehydrochloride 0.05%, naphazoline hydrochloride 0.03%, tetrahydrozolinehydrochloride 0.05%, and phenylephrine hydrochloride 1.0%, and wasobserved, though less pronounced, on the site pretreated withbrimonidine tartrate 0.2% alone, and the site pretreated withoxymetazoline hydrochloride 0.05%+brimonidine tartrate 0.2%). No localor systemic side effects were noted, and in particular, there was norebound erythema or edema noted.

These trials demonstrate that selective α₁ adrenergic receptor agonistsand selective α₂ adrenergic receptor agonists, used separately or incombination, when topically applied prior to a procedure that can/willinduce purpura, will reduce the size and appearance of the purpuricmacules/patches and is an effective treatment to hasten theirresolution.

EXAMPLE 3

The use of a topically applied α₂ adrenergic agonist for the treatmentand prevention of solar purpura (“actinic purpura”, “Bateman'spurpura”): In order to evaluate the effect of topically applied α₁ andα₂ adrenergic agonists on the prevention and treatment of solar purpura,a 78 year old male volunteer with a diagnosis of solar purpura of theforearms treated with a topically applied α₂ adrenergic agonistcontaining solution. The test area comprised the right extensor forearmfrom the wrist to the elbow. Photos were taken and baseline scores forthe solar purpura on his right dorsal forearm from the wrist to theelbow were measured 6 times over a 91 day period before initiatingtreatment. Two measurements were taken to approximate the area of eachpurpuric patch. The measurements ranged from 0 cm² to 9.98 cm² and themean over 6 measurements was 3.67 cm². (See Table 1)

A solution of brimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing:brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodiumchloride, sodium citrate, purified water, and benzalkonium chloride(0.005%) was applied by the patient to the right dorsal forearm twicedaily (morning and evening). The solution was applied with a cotton ballto the skin of the entire right extensor forearm from the wrist to theelbow. The sites were followed clinically and photographically.

Seven days after starting, the patient returned for evaluation. Thetotal area of purpura on the right dorsal forearm were measured andequaled 1.48 cm² (a decrease of 60% compared to mean baseline). Thepatient continued to apply brimonidine 0.2% solution to the right dorsalforearm twice daily (morning and evening).

Fourteen days after starting, the patient returned for evaluation. Thetotal area of purpura on the right dorsal forearm were measured andequaled 0.35 cm² (a decrease of 90% compared to mean baseline). Thepatient continued to apply brimonidine 0.2% solution to the right dorsalforearm twice daily (morning and evening).

Twenty four days after starting, the patient returned for evaluation.The total area of purpura on the right dorsal forearm were measured andequaled 5.72 cm² (an increase of 34% compared to mean baseline). Thepatient reported that he had recently been gardening and had notedsignificant increase in the purpura after this activity despitecontinuing the topical medication. The patient continued to applybrimonidine 0.2% solution to the right dorsal forearm twice daily(morning and evening).

Thirty six days after starting, the patient returned for evaluation. Thetotal area of purpura on the right dorsal forearm were measured andequaled 2.52 cm² (a decrease of 31% compared to mean baseline).

TABLE 1 Day Purpura Area(cm²) Effect Notes 0 3.67 — Baseline 7 1.48 ↓60% from Baseline 14 0.35 ↓ 90% from Baseline 24 5.72 ↑ 34% fromBaseline ↑ in purpura noted after gardening 36 2.52 ↓ 31% from Baseline

This trial demonstrates that the selective α₂ adrenergic receptoragonist 0.2% brimonidine tartrate when topically applied twice daily toareas effected by solar (“actinic” or “senile” or “Bateman's”) purpurareduces the size and appearance of purpuric macules/patches. Thoughsignificant intervening trauma to the region being treated (e.g. traumato the arms from gardening) may still induce purpura, it is shown to bean effective treatment to hasten the resolution and decrease theappearance of purpura in actinically damaged or otherwiseatrophic/damaged skin and cutaneous vessels.

EXAMPLE 4

The use of a topically applied α₁ adrenergic agonist for the treatmentand prevention of solar purpura: In order to evaluate the effect oftopically applied α₁ adrenergic agonists on the prevention and treatmentof solar purpura, two patient volunteers with the diagnosis of solarpurpura of the forearms were treated with a topically applied selectiveα₁ adrenergic agonist containing solution.

Subject 1 is a 78 year old man with a long-standing history of solarpurpura on his forearms. The test area comprised the left dorsal(extensor) forearm from the wrist to the elbow. Pretreatment photos weretaken and baseline measurements of the solar purpura on the leftextensor forearm from the wrist to the elbow were measured. Twomeasurements were taken to approximate the area of each purpuric patch.The total area of purpura was 8.94 cm². (SEE TABLE 2)

A solution of oxymetazoline hydrochloride 0.05% (Afrin® Original 12 HourNasal Spray (Schering-Plough Healthcare Products) containing:oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,edetate disodium, polyethylene glycol, povidone, propylene glycol,purified water, sodium phosphate dibasic, sodium phosphate monobasic(0.005%)) was applied by the patient to the left dorsal forearm twicedaily (morning and evening). The solution was applied with a cotton ballto the skin of the entire extensor forearm from the wrist to the elbow.The sites were followed clinically and photographically.

Seventeen days later, the patient returned for evaluation. The totalarea of purpura on the left extensor forearm were measured and equaled9.95 cm² (an increase of 11% compared to baseline). The patientcontinued to apply oxymetazoline solution 0.05% to the left dorsalforearm twice daily (morning and evening).

Twenty nine days after starting, the patient returned for evaluation.The total area of purpura on the left extensor forearm were measured andequaled 5.73 cm² (a decrease of 36% compared to baseline). The patientcontinued to apply oxymetazoline solution 0.05% to the left dorsalforearm twice daily (morning and evening).

Forty four days after starting, the patient returned for evaluation. Thetotal area of purpura on the left extensor forearm were measured andequaled 5.6 cm² (a decrease of 37% compared to baseline). The patientcontinued to apply oxymetazoline solution 0.05% to the left dorsalforearm twice daily (morning and evening).

Eighty one days after starting, the patient returned for evaluation. Thetotal area of purpura on the left extensor forearm were measured andequaled 1.44 cm² (a decrease of 84% compared to baseline). The patientcontinued to apply oxymetazoline solution 0.05% to the left dorsalforearm twice daily (morning and evening).

Ninety one days after starting, the patient returned for evaluation. Thetotal area of purpura on the left extensor forearm were measured andequaled 0.42 cm² (a decrease of 95% compared to baseline). The patientstopped applying the oxymetazoline containing solution on study day 91.

Seven days after stopping the oxymetazoline, the total area of purpuraon the left extensor forearm was measured and equaled 1.96 cm². (anincrease of 366% from the point of stopping medication (day 91measurement)).

Fourteen days after stopping the oxymetazoline, the total area ofpurpura on the left extensor forearm was measured and equaled 0.46 cm².(an increase of 10% from the point of stopping medication (day 91measurement)).

Twenty four days after stopping the oxymetazoline, the total area ofpurpura on the left extensor forearm was measured and equaled 2.22 cm².(an increase of 428% from the point of stopping medication (day 91measurement)).

TABLE 2 Day Purpura Area(cm²) Effect Notes 0 8.94 — Baseline 17 9.95 ↑11% from Baseline 29 5.73 ↓ 36% from Baseline 44 5.6 ↓ 37% from Baseline81 1.44 ↓ 84% from Baseline 91 0.42 ↓ 95% from Baseline MedicationDiscontinued Day 91 98 1.96 ↑ 366% from Baseline 7 Days off Medication112 0.46 ↑ 10% from Baseline 14 Days off Medication 122 2.22 ↑ 428% fromBaseline 24 Days off Medication

The patient stated that he felt that there were fewer new purpuricmacules/patches while he was using the medication, and he felt that whenpurpura occurred they seemed to resolve more quickly. The patient had noside effects, either local or systemic, during the treatment.

Subject 2 is an 87 year old woman with a long history of cosmeticallydisturbing solar purpura on her forearms who wanted to improve theappearance solar (decrease the purpura). The test area comprised theleft dorsal (extensor) forearm from the wrist to the elbow. Pretreatmentphotos were taken and baseline measurements of the solar purpura on theleft extensor forearm from the wrist to the elbow were measured. Twomeasurements were taken to approximate the area of each purpuric patch.The total area of purpura was 1.72 cm². (SEE TABLE 3)

A solution of oxymetazoline hydrochloride 0.05% (Afrin® Original 12 HourNasal Spray (Schering-Plough Healthcare Products) containing:oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,edetate disodium, polyethylene glycol, povidone, propylene glycol,purified water, sodium phosphate dibasic, sodium phosphate monobasic(0.005%)) was applied by the patient to the left dorsal forearm oncedaily (morning). The solution was applied with a cotton ball to the skinof the entire extensor forearm from the wrist to the elbow. The siteswere followed clinically and photographically.

7 days later, the patient was reevaluated. The total area of purpura onthe left dorsal forearm measured 0 cm² (a decrease of 100% compared tobaseline). The patient continued to apply oxymetazoline solution 0.05%to the left extensor forearm once daily (morning).

31 days after starting, the patient was reevaluated. The total area ofpurpura on the left dorsal forearm measured 0 cm² (a decrease of 100%compared to baseline). The patient continued to apply oxymetazolinesolution 0.05% to the left extensor forearm once daily (morning).

36 days after starting, the patient was reevaluated. The total area ofpurpura on the left extensor forearm measured 0.36 cm² (a decrease of79% compared to baseline).

TABLE 3 Day Purpura Area(cm²) Effect Notes 0 1.72 — Baseline 7 0.00 ↓100% from Baseline 31 0.00 ↓ 100% from Baseline 36 0.36 ↓ 79% fromBaseline

The patient stated that she felt that there were fewer new purpuricpatches while she was using the medication, and in her estimation thepurpura that did occur seemed to resolve more quickly. The patient hadno side effects, either local or systemic, during the treatment.

These trials demonstrate that the selective α₁ adrenergic receptoragonist oxymetazoline hydrochloride when topically applied once or twicedaily to areas effected by solar purpura dramatically reduces the sizeand appearance of purpuric macules/patches and may eliminate them.Though continuing trauma to the region being treated (e.g. trauma to thearms from gardening) may still induce purpura, this treatment is shownto be an effective treatment to hasten the resolution and decrease theappearance of purpura in actinically damaged or otherwiseatrophic/damaged skin and cutaneous vessels.

1. A method for treating purpura in a subject comprising administering atherapeutically effective amount of an α adrenergic receptor agonist. 2.The method of claim 1, wherein the α adrenergic receptor agonist istopically applied to the skin of the subject.
 3. The method of claim 1,wherein the α adrenergic receptor agonist is locally delivered to thesubject.
 4. The method of claim 1, wherein the α adrenergic receptoragonist is selected from a selective α₁ adrenergic receptor agonist, aselective α₂ adrenergic receptor agonist, a non-selective α₁/α₂adrenergic receptor agonist, an agent with α₂ adrenergic receptoragonist activity and combinations thereof.
 5. The method of claim 1wherein the α adrenergic agonist is selected from oxymetazoline,naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 6. Themethod of claim 4, wherein the selective α₁ adrenergic receptor agonistis selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, amidephrine and combinations thereof. 7.The method of claim 4, wherein the selective α₁-adrenergic receptoragonist is selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine hydrochloride and combinations thereof.
 8. The method ofclaim 4, wherein the selective α₂ adrenergic receptor agonist isselected from brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,and combinations thereof.
 9. The method of claim 4, wherein theselective α₂-adrenergic receptor agonist is brimonidine.
 10. The methodof claim 4, wherein the non-selective α₁/α₂ adrenergic receptor agonistis selected from epinephrine, norepinephrine, isoproterenol, dipivefrin,pseudoephedrine, mephentermine and combinations thereof.
 11. The methodof claim 4, wherein the agent with α₂ adrenergic receptor agonistactivity is selected from phenylpropanolamine, propylhexadrine,amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 12. Themethod of claim 1 further comprising administering a therapeuticallyeffective amount of at least one other active agent selected fromantibacterial agents, antiparasitic agents, antifungal agents,anti-inflammatory agents, antihistamines, anti-pruriginous agents,anesthetics, antiviral agents, keratolytic agents, anti free-radicalagents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A,superoxide dismutase derivatives of plants, sesquiterpene lactones,antiseborrheic agents, antidandruff agents, antiacne agents, sunscreensand sun blocking agents, and active agents which modify at least one ofcutaneous differentiation, proliferation, and pigmentation, includingbut not limited to tretinoin, retinol, retinal, alpha hydroxyl acids,beta hydroxyl acids and combinations thereof.
 13. The method of claim 1,wherein said α adrenergic receptor agonist is administered in apharmacologically acceptable form selected from solutions, gels, lotionscreams, ointments, foams, emulsions, microemulsions, milks, serums,aerosols, sprays, dispersions, microcapsules, vesicles andmicroparticles thereof, soaps, and cleansing bars.
 14. A method fordecreasing purpura in a subject comprising administering atherapeutically effective amount of an α adrenergic receptor agonist.15. The method of claim 14, wherein the α adrenergic receptor agonist istopically applied to the skin of the subject.
 16. The method of claim14, wherein the α adrenergic receptor agonist is locally delivered tothe subject.
 17. The method of claim 14, wherein the α adrenergicreceptor agonist is selected from a selective α₁ adrenergic receptoragonist, a selective α₂ adrenergic receptor agonist, a non-selectiveα₁/α₂ adrenergic receptor agonist, an agent with α₂ adrenergic receptoragonist activity and combinations thereof.
 18. The method of claim 14wherein the α adrenergic agonist is selected from oxymetazoline,naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 19. Themethod of claim 17, wherein the selective α₁ adrenergic receptor agonistis selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, amidephrine and combinations thereof. 20.The method of claim 17, wherein the selective α₁-adrenergic receptoragonist is selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine hydrochloride and combinations thereof.
 21. The method ofclaim 17, wherein the selective α₂ adrenergic receptor agonist isselected from brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,and combinations thereof.
 22. The method of claim 17, wherein theselective α₂-adrenergic receptor agonist is brimonidine.
 23. The methodof claim 17, wherein the non-selective α₁/α₂ adrenergic receptor agonistis selected from epinephrine, norepinephrine, isoproterenol, dipivefrin,pseudoephedrine, mephentermine and combinations thereof.
 24. The methodof claim 17, wherein the agent with α₂ adrenergic receptor agonistactivity is selected from phenylpropanolamine, propylhexadrine,amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 25. Themethod of claim 14 further comprising administering a therapeuticallyeffective amount of at least one other active agent selected fromantibacterial agents, antiparasitic agents, antifungal agents,anti-inflammatory agents, antihistamines, anti-pruriginous agents,anesthetics, antiviral agents, keratolytic agents, anti free-radicalagents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A,superoxide dismutase derivatives of plants, sesquiterpene lactones,antiseborrheic agents, antidandruff agents, antiacne agents, sunscreensand sun blocking agents, and active agents which modify at least one ofcutaneous differentiation, proliferation, and pigmentation, includingbut not limited to tretinoin, retinol, retinal, alpha hydroxyl acids,beta hydroxyl acids and combinations thereof.
 26. The method of claim14, wherein said α adrenergic receptor agonist is administered in apharmacologically acceptable form selected from solutions, gels, lotionscreams, ointments, foams, emulsions, microemulsions, milks, serums,aerosols, sprays, dispersions, microcapsules, vesicles andmicroparticles thereof, soaps, and cleansing bars.
 27. A method fordecreasing purpura in a subject prior to a surgical procedure comprisingadministering a therapeutically effective amount of an α adrenergicreceptor agonist to the site of said surgical procedure.
 28. The methodof claim 27, wherein the α adrenergic receptor agonist is topicallyapplied to said site of said surgical procedure.
 29. The method of claim27, wherein the α adrenergic receptor agonist is locally delivered tothe site of said surgical procedure.
 30. The method of claim 27, whereinthe α adrenergic receptor agonist is selected from a selective α₁adrenergic receptor agonist, a selective α₂ adrenergic receptor agonist,a non-selective α₁/α₂ adrenergic receptor agonist, an agent with α₂adrenergic receptor agonist activity and combinations thereof.
 31. Themethod of claim 27, wherein the α adrenergic agonist is selected fromoxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine,cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 32. Themethod of claim 30, wherein the selective α₁ adrenergic receptor agonistis selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,desglymidodrine, cirazoline, amidephrine and combinations thereof. 33.The method of claim 30, wherein the selective α₁-adrenergic receptoragonist is selected from oxymetazoline, naphazoline, tetrahydrozoline,phenylephrine hydrochloride and combinations thereof.
 34. The method ofclaim 30, wherein the selective α₂ adrenergic receptor agonist isselected from brimonidine, clonidine, guanfacine, guanabenz,apraclonidine, xylazine, medetomidine, dexmedetomidine, α-methyldopa,and combinations thereof.
 35. The method of claim 30, wherein theselective α₂-adrenergic receptor agonist is brimonidine.
 36. The methodof claim 30, wherein the non-selective α₁/α₂ adrenergic receptor agonistis selected from epinephrine, norepinephrine, isoproterenol, dipivefrin,pseudoephedrine, mephentermine and combinations thereof.
 37. The methodof claim 30, wherein the agent with α₂ adrenergic receptor agonistactivity is selected from phenylpropanolamine, propylhexadrine,amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,levarterenol, lofexidine, methamphetamine, α-methylnorepinephrine,methylphenidate, mivazerol, moxonidine, norepinephrine,norphenylephrine, pemoline, tizanidine and combinations thereof.
 38. Themethod of claim 27 further comprising administering a therapeuticallyeffective amount of at least one other active agent selected fromantibacterial agents, antiparasitic agents, antifungal agents,anti-inflammatory agents, antihistamines, anti-pruriginous agents,anesthetics, antiviral agents, keratolytic agents, anti free-radicalagents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A,superoxide dismutase derivatives of plants, sesquiterpene lactones,antiseborrheic agents, antidandruff agents, antiacne agents, sunscreensand sun blocking agents, and active agents which modify at least one ofcutaneous differentiation, proliferation, and pigmentation, includingbut not limited to tretinoin, retinol, retinal, alpha hydroxyl acids,beta hydroxyl acids and combinations thereof.
 39. The method of claim27, wherein said α adrenergic receptor agonist is administered in apharmacologically acceptable form selected from solutions, gels, lotionscreams, ointments, foams, emulsions, microemulsions, milks, serums,aerosols, sprays, dispersions, microcapsules, vesicles andmicroparticles thereof, soaps, and cleansing bars.
 40. The method ofclaim 27, wherein said surgical procedure is a laser treatment.
 41. Themethod of claim 27, wherein said therapeutically effective amount of anα adrenergic receptor agonist is administered prior to said surgicalprocedure.
 42. The method of claim 27, wherein said therapeuticallyeffective amount of an α adrenergic receptor agonist is administeredduring said surgical procedure
 43. The method of claim 27, wherein saidtherapeutically effective amount of an α adrenergic receptor agonist isadministered after said surgical procedure.